Increased chemoresistance via Snail-Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative.
Increased chemoresistance via Snail-Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative.
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DOI：
10.18632/oncotarget.8049
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Liu TY
中科院分区：
文献类型：
--
作者：
Lee TY;Liu CL;Chang YC;Nieh S;Lin YS;Jao SW;Chen SF;Liu TY
烟草特有的成分 4-甲基亚硝基氨基-1-3-吡啶基-1-丁酮 (NNK) 是许多癌症的主要危险因素。最近的报告表明，NNK 暴露可能与某些癌症的肿瘤进展和化疗耐药有关。然而，NNK 诱导的导致结直肠癌 (CRC) 侵袭性的潜在机制尚未得到彻底研究。在本研究中，我们使用经过 NNK 处理的 HT29 细胞来模拟长期暴露于香烟烟雾。进行比较分析以评估细胞增殖、迁移和侵袭以及上皮间质转化（EMT）标记和耐药基因表达、癌症干细胞（CSC）特性和抗凋亡活性。还研究了与化疗耐药相关的信号通路。因此，NNK 暴露剂量依赖性地刺激细胞增殖、增强迁移和侵袭能力、诱导 EMT 现象并减弱细胞凋亡。此外，NNK 暴露还促进球体形成的能力、Snail 的上调以及 CD133、Nanog、OCT4 和耐药基因的过度表达。 Snail 的敲低会导致 Raf 激酶抑制剂蛋白 (RKIP) 上调、细胞凋亡增加、EMT 现象逆转以及 CSC 标记物表达减少，所有这些都有助于降低化疗耐药性。我们的研究证明了许多相关机制，这些机制通过 Snail 信号通路介导 NNK 暴露对增加 CRC 治疗耐药性的影响。靶向 Snail 可能为 CRC 的治疗提供可行的策略。
A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.
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影响因子：
5.2
作者：
Xue J;Yang S;Seng S
通讯作者：
Seng S
影响因子：
3.7
作者：
Chen SF;Lin YS;Jao SW;Chang YC;Liu CL;Lin YJ;Nieh S
通讯作者：
Nieh S
DOI：
10.1152/ajpgi.00138.2012
发表时间：
2012-09-01
影响因子：
4.5
作者：
Alexandre, M.;Uduman, A. K.;Thrower, E. C.
通讯作者：
Thrower, E. C.
影响因子：
6.4
作者：
Chang, Yun-Ching;Nieh, Shin;Fu, Earl
通讯作者：
Fu, Earl
影响因子：
4.9
作者：
Grothey, Axel
通讯作者：
Grothey, Axel